We have replicated the results of a preliminary outpatient study showing that treatment with alpha-tocopherol (vitamin E) decreases symptoms of tardive dyskinesia (TD). This supports the free radical hypothesis of TD. We are planning several additional studies to further explore the neurobiology of TD. These include trials of medications, neuropsychological tests, neuroradiological examinations, evaluations of eye tracking and the neurochemistry of an animal model of TD. We are studying the following three hypotheses: (1) agents that reduce free radicals also reduce the severity of and prevent the development of TD; (2) TD is associated with altered outflow of striatonigral and striatopallidal efferent pathways, possibly due to neuronal cell loss; and (3) cognitive impairment is associated with TD in older but not younger patients relative to patients without TD.